rs63750072

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377265.1(MAPT):c.914A>G(p.Gln305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,611,384 control chromosomes in the GnomAD database, including 2,247 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 144 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2103 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 2.48

Publications

26 publications found

Variant links:

Genes affected

MAPT (HGNC:6893): (microtubule associated protein tau) This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]

MAPT Gene-Disease associations (from GenCC):

Pick disease
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
late-onset Parkinson disease
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

MAPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003071189).

BP6

Variant 17-45983493-A-G is Benign according to our data. Variant chr17-45983493-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 98197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.914A>G	p.Gln305Arg	missense_variant	Exon 5 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.914A>G	p.Gln305Arg	missense_variant	Exon 5 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5911

AN:

152038

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0260

Gnomad EAS

AF:

0.0151

Gnomad SAS

AF:

0.0437

Gnomad FIN

AF:

0.0263

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0559

GnomAD2 exomes

AF:

0.0396

AC:

9703

AN:

244776

AF XY:

0.0420

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0304

Gnomad EAS exome

AF:

0.0157

Gnomad FIN exome

AF:

0.0260

Gnomad NFE exome

AF:

0.0528

Gnomad OTH exome

AF:

0.0583

GnomAD4 exome

AF:

0.0500

AC:

72947

AN:

1459228

Hom.:

2103

Cov.:

AF XY:

0.0503

AC XY:

36521

AN XY:

725738

show subpopulations

African (AFR)

AF:

0.0121

AC:

404

AN:

33448

American (AMR)

AF:

0.0267

AC:

1190

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

752

AN:

26068

East Asian (EAS)

AF:

0.0147

AC:

582

AN:

39650

South Asian (SAS)

AF:

0.0473

AC:

4076

AN:

86166

European-Finnish (FIN)

AF:

0.0293

AC:

1531

AN:

52226

Middle Eastern (MID)

AF:

0.128

AC:

734

AN:

5748

European-Non Finnish (NFE)

AF:

0.0546

AC:

60674

AN:

1110964

Other (OTH)

AF:

0.0498

AC:

3004

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

4396

8793

13189

17586

21982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0388

AC:

5908

AN:

152156

Hom.:

144

Cov.:

AF XY:

0.0375

AC XY:

2790

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0134

AC:

558

AN:

41550

American (AMR)

AF:

0.0398

AC:

608

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

AN:

3468

East Asian (EAS)

AF:

0.0151

AC:

AN:

5160

South Asian (SAS)

AF:

0.0444

AC:

214

AN:

4822

European-Finnish (FIN)

AF:

0.0263

AC:

279

AN:

10612

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0567

AC:

3854

AN:

67932

Other (OTH)

AF:

0.0553

AC:

117

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

267

533

800

1066

1333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0509

Hom.:

763

Bravo

AF:

0.0389

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0516

AC:

199

ESP6500AA

AF:

0.0160

AC:

ESP6500EA

AF:

0.0551

AC:

471

ExAC

AF:

0.0392

AC:

4750

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0623

EpiControl

AF:

0.0565

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Aug 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29339765) -

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1

Benign:1

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Frontotemporal dementia

Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;.;T

Eigen

Benign

0.066

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.65

T;T;.;.

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

2.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Benign

0.079

Sift

Uncertain

0.0020

D;D;D;.

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.99

D;D;D;D

Vest4

0.095

MPC

0.17

ClinPred

0.019

GERP RS

4.1

Varity_R

0.090

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs63750072

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over